Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study

Abstract

PurposeAgents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC.MethodsIn a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx).ResultsA total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2–50 weeks and followed for 6–15 months. Patients were heavily pretreated with a median of three prior therapies for metastatic or locally advanced disease. Grade ≥ 3 treatment-related AEs occurred in 13.7% of patients, including two treatment-related deaths. The confirmed objective response rate (ORR) was 3.0% overall (one complete response and four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1− tumor-associated immune cells in the overall population (16.7% vs. 1.6%) and in the TNBC subgroup (22.2% vs. 2.6%).ConclusionAvelumab showed an acceptable safety profile and clinical activity in a subset of patients with MBC. PD-L1 expression in tumor-associated immune cells may be associated with a higher probability of clinical response to avelumab in MBC.

Immunotherapy for Breast Cancer: What Are We Missing?

“…Further investigation is required to understand if these patients with a clinical response were enriched for TNBC patients with detectable levels of PD-L1 in the tumor (2). In an unselected cohort of 168 breast cancer patients, the anti-PD-L1 antibody avelumab showed an ORR of only 4.8%; most of the responders were those with TNBC in this cohort (2, 42). In this study, known as JAVELIN, patients with PD-L1 expression on immune cells in the tumor showed greater overall response than patients with PD-L1-negative immune cells (4 of 12, or 33.3% vs. 3 of 124, or 2.4%); in TNBC patients, PD-L1 expression also appeared to be associated with response (4 of 9, or 44%, for PD-L1 positive patients vs. 1 of 39, or 2.0%, for PD-L1 negative patients) (42).…”

“…In an unselected cohort of 168 breast cancer patients, the anti-PD-L1 antibody avelumab showed an ORR of only 4.8%; most of the responders were those with TNBC in this cohort (2, 42). In this study, known as JAVELIN, patients with PD-L1 expression on immune cells in the tumor showed greater overall response than patients with PD-L1-negative immune cells (4 of 12, or 33.3% vs. 3 of 124, or 2.4%); in TNBC patients, PD-L1 expression also appeared to be associated with response (4 of 9, or 44%, for PD-L1 positive patients vs. 1 of 39, or 2.0%, for PD-L1 negative patients) (42). Clinical trials combining PD-1/PD-L1 antibodies with other therapies such as trastuzumab or anti-estrogens are underway, including in the neoadjuvant and adjuvant settings.…”

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

“…But PD-L1 expression is associated with HER2 + status and there is an independent poor prognostic impact of PD-L1 in HER2 + BCs (132)(133)(134). In a phase 1b trial which 168 patients with MBC received avelumab, avelumab showed an acceptable clinical activity (135). Currently, many clinical trials in HER2 + cohort are ongoing, such as NCT02648477 and NCT02129556 for pembrolizumab, NCT02605915 for atezolizumab and NCT02649686 for durvalumab (131).…”

Neoadjuvant Model as a Platform for Research in Breast Cancer and Novel Targets under Development in this Field

“…In the metastatic setting, treatment with anti-programmed cell death protein ligand 1 (PD-L1) drugs such as pembrolizumab or avelumab has shown poor efficacy [37,38]. The ULTIMATE study is trying to challenge these concepts (NCT02997995); the study includes 2 therapeutic sequences: in the first part, patients receive a single infusion of tremelimumab as an immune-attractant plus exemestane; and in the second part, CD8+ patients (tumor CD8 infiltration > 10%) receive 6 months of durvalumab, another anti-PD-L1 agent, also with exemestane.…”